The present invention relates to substituted 3-amino-3-arylpropan-1-ols of the general formula I, 
wherein
R1, R2 denote, in each case independently of one another, C1-6 alkyl or R1 and R2 together denote a (CH2)2-6 ring that may also be substituted by phenyl,
R3 denotes C3-6 alkyl, C3-6 cycloalkyl, aryl with optionally heteroatoms in the ring system and the substituents R6 to R8 on the aryl ring, or a substituted C1-3 alkylphenyl of the formula XII, 
xe2x80x83wherein
n=1, 2 or 3
R4, R5 denote, in each case independently of one another, C1-6 alkyl, C3-6 cycloalkyl, phenyl, benzyl, phenethyl or R4 and R5 together form a (CH2)3-6 ring or CH2CH2OCH2CH2 ring,
R6 to R8 denote, in each case independently of one another, H, F, Cl, Br, CHF2, CF3, OH, OCF3, OR14, NR15R16, SR14, phenyl, SO2CH3, SO2CF3, C1-6 alkyl, CN, COOR14, CONR15R16 or R6 and R7 together form a OCH2O, OCH2CH2O, CHxe2x95x90CHO, CHxe2x95x90C(CH3)O or (CH2) ring, wherein
R14 denotes C1-6 alkyl, phenyl, benzyl, phenethyl and
R15, R16 denote, in each case independently of one another, H, C1-6 alkyl, phenyl, benzyl, phenethyl, and
A denotes an aryl radical that may optionally contain heteroatoms in the ring system and/or that may optionally be substituted,
and their diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids, whereas 1-benzyl-2-(dimethylaminophenylmethyl)cyclohexanol, its diastereomers and its enantiomers in the form of their bases and its reaction product with methyliodide are disclaimed, as well as their preparation and use as medicinal drugs.
The treatment of chronic and non-chronic painful states is extremely important in medicine since pain is one of the basic symptoms encountered in clinical practice. At the present time there is a worldwide demand for additional, not exclusively opioid, but highly effective pain treatments.
The urgent need for a patient-friendly and targeted treatment of chronic and non-chronic painful states, by which is meant the successful and satisfactory management of pain for the patient, is documented in the large number of scientific articles that have recently appeared in the field of applied analgesics and fundamental research in nociception.
Conventional opioids such as for example morphine are extremely effective in treating severe to extremely severe pain. Their use is limited however by the known side effects, for example respiratory depression, vomiting, sedation, constipation, addiction, dependence and development of tolerance. Accordingly they can be administered over a prolonged period or in relatively high doses only if particular safety precautions, for example special regulatory provisions, are observed (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York, 1990). Furthermore, they are less effective in some painful states, in particular in the case of neuropathic pain.
The object forming the basis of the present invention is to provide a new structural class of analgesically effective substances that are suitable for treating pain. Further objects of the invention are to provide active agents that are also suitable for use as a local anaesthetic and/or anti-arrythmic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence and/or inflammation. As a rule the substances are also suitable for treating depression and/or for improving alertness and attentiveness, and/or improving libido.
It has now been found that the class of compounds of the general formula I is characterized by a pronounced analgesic action. Furthermore the compounds of the general formula I exhibit a marked affinity for the binding site 2 of the sodium channel (BTX binding), for the benzothiazepine and the phenylalkylamine binding site of the L-type calcium channel (diltiazem and verapamil binding), and inhibit synaptosomal noradrenaline uptake (NA uptake inhibition). Accordingly the class of compounds of the general formula I is also suitable for use as a local anaesthetic and/or anti-arrythmic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence, and/or inflammation. As a rule the class of compounds of the general formula I is also suitable for improving alertness and attentiveness and/or improving libido and/or for treating depression.
The invention thus relates to substituted 3-amino-3-arylpropan-1-ols of the general formula I, 
wherein the radicals R1 to R5 and A have the meanings given above,
and the corresponding diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids,
whereas 1-benzyl-2-(dimethylaminophenylmethyl)cyclohexanol, its diastereomers and its enantiomers in the form of their bases and its reaction product with methyliodide are disclaimed.
Preferred are compounds of the general formula I in which R1 and R2 together form a (CH2)2-6 ring, in particular a (CH2)4 ring, which is optionally substituted by phenyl, R3 to R5 and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R3 denotes a substituted C1-3 alkylphenyl of the formula XII, R1, R2, R4 and R5 and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R6 to R8 on the aryl ring, R1, R2, R4 and R5 and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which A denotes a radical from the group of substituted phenyl of the formula XI 
xe2x80x83wherein
R9 to R13 denote, in each case independently of one another, H, F, Cl, Br, I, CF3, OH, OR14, OCF3, SR14, SO2CH3, SO2CF3, C1-6 alkyl, phenyl, CN, COOR14, NO2 or R9 and R10 or R10 and R11 together form a OCH2O or OCH2CH2O ring,
R14 denotes C1-6 alkyl, phenyl, benzyl, phenethyl
or A denotes an unsubstituted or substituted thiophene or an unsubstituted or substituted furan, and the radicals R1 to R5 have the meanings according to the definition of the general formula I.
Also preferred are compounds of the general formula I in which R1 and R2 together form a (CH2)2-6 ring, in particular a (CH2)4 ring, which is optionally substituted by phenyl, R3 denotes a substituted C1-3 alkylphenyl of the formula XII, R4 to R5 and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R1 and R2 together form a (CH2)2-6 ring, in particular a (CH2)4 ring, which is optionally substituted by phenyl, R3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R6 to R8 on the aryl ring, and R4 to R5 and A have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R1 and R2 together form a (CH2)4 ring, which is optionally substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstituted or substituted furan, R3denotes a substituted C1-3 alkylphenyl of the formula XII, and R4 to R5 have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R1 and R2 together form a (CH2)4 ring, which is optionally substituted by phenyl, A denotes a radical from the group of substituted phenyl of the formula XI or unsubstituted or substituted thiophene or unsubstituted or substituted furan, R3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R6 to R8 on the aryl ring, and R4 to R5 have the meanings according to the definition of the general formula I.
Also preferred are compounds of the general formula I in which R1 and R2 together form a (CH2)4 ring, A denotes unsubstituted or substituted thiophene, R3 denotes a substituted C1-3 alkylphenyl of the formula XII, and R4 to R5 have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R1 and R2 together form a (CH2)4 ring, A denotes unsubstituted or substituted thiophene, R3denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R6 to R8 on the aryl ring, and R4 to R5 have the meanings according to the definition of the general formula I, or
compounds of the general formula I in which R1 and R2 together form a (CH2)4 ring, A denotes unsubstituted or substituted furan, R3 denotes a substituted C1-3 alkylphenyl of the formula XII, and R4 to R5 have the meanings according to the definition of the general formula I.
Compounds of the general formula I in which R1 and R2 together form a (CH2)4 ring A denotes unsubstituted or substituted furan, R3 denotes an aryl radical with optionally heteroatoms in the ring system and the substituents R6 to R8 on the aryl ring, and R4 to R5 have the meanings according to the definition of the general formula I.
Substituents on the substituted thiophene radicals or substituted furan radicals are preferably selected from the group consisting of C1-6 alkyl, halogen (particularly preferably Br, Cl or F), OR, SR, aryl SO2R, NO2, CN and COOR,
wherein R is C1-6 alkyl. More than one substituent may be present on the substituted thiophene or furan radicals, but preferably the substituted thiophene and furan radicals are monosubstituted.
Further preferred compounds include:
2-(dimethylaminophenylmethyl)-1-(3-methoxyphenyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(3-fluorophenyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-phenylcyclohexanol and the corresponding hydrochloride
3-[2-(dimethylaminophenylmethyl)-1-hydroxycyclohexyl]phenol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-methoxyphenyl)cyclohexanol and the corresponding hydrochloride
1-(4-chlorophenyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-fluorophenyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-p-tolylcyclohexanol and the corresponding hydrochloride
1-(3-chlorophenyl)-2-[dimethylamino-(3-methoxyphenyl)-methyl]cyclohexanol and the corresponding hydrochloride
1-(4-dimethylaminophenyl)-2-(dimethylaminophenyl-methyl)cyclohexanol and the corresponding hydrochloride
1-benzo[1,3]dioxol-4-yl-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
1-(3,4-dimethoxyphenyl)-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(3-methoxybenzyl)-cyclohexanol and the corresponding hydrochloride
1-benzyl-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-fluoro-3-trifluoromethylphenyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-trifluoromethoxybenzyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-furan-3-ylcyclolexanol and the corresponding hydrochloride
1-butyl-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-(3,4-dichlorophenyl)-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
(+)-1-(3,4-dichlorophenyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
(xe2x88x92)-1-(3,4-dichlorophenyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
4-[2-(dimethylaminophenylmethyl)-1-hydroxycyclohexyl]-phenol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-naphthalene-2-ylcyclohexanol] and the corresponding hydrochloride
2-[dimethylamino-(4-trifluoromethylphenyl)methyl]-1-(3-methoxybenzyl)cyclohexanol and the corresponding hydrochloride
1-(4-chlorobenzyl)-2-(dimethylaminophenylmethyl)-1-cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(2-fluorobenzyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-fluorobenzyl)cyclohexanol and the corresponding hydrochloride 1-(2,5-dimethoxyphenyl)-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
1-(2-chloro-4-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclolhexanol and the corresponding hydrochloride
1-(4-tert.-butylbenzyl)-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(3-fluorobenzyl)cyclohexanol and the corresponding hydrochloride
1-(2-chlorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-benzo[1,3]dioxol-5-yl-2-[dimethylamino(3-methoxyphenyl)methyl]cyclohexanol and the corresponding hydrochloride
1-(3-chlorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-(2,4-dichlorobenzyl)-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[dimethylaminophenyl-(3-phenoxyphenyl)-methyl]cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[dimethylaminophenyl-(3-methoxyphenyl)-methyl]cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(3-trifluoromethylbenzyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylamino-(3-methoxyphenyl)methyl]-1-(3-methoxybenzyl)cyclohexanol and the corresponding hydrochloride
2-[(2-chlorophenyl)dimethylaminomethyl]-1-naphthalene-2-ylcyclohexanol and the corresponding hydrochloride
1-benzyl-2-[(3,4-dichlorophenyl)dimethylaminomethyl]-cyclohexanol and the corresponding hydrochloride
2-[(3,4-dichlorophenyl)(dimethylaminomethyl]-1-phenethyl-cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[dimethylamino-(4-fluorophenyl)methyl]cyclohexanol and the corresponding hydrochloride
2-[(3-chlorophenyl)(dimethylaminomethyl]-1-phenyl-cyclohexanol and the corresponding hydrochloride
1-(2,4-dichlorophenyl)-2-(3-dimethylaminomethyl)-1-cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[(3-chlorophenyl)dimethylaminomethyl]cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[(2-chlorophenyl)dimethylaminomethyl]cyclohexanol and the corresponding hydrochloride
1-(4-tert.-butylbenzyl)-2-[(3,4-dichlorophenyl)dimethylaminometlhyl)cyclohexanol and the corresponding hydrochloride
2-[dimethylamino-(4-fluorophenyl)methyl]-1-(3-trifluoromethylbenzyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)bicyclohexyl-1-ol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-methoxybenzyl)-cyclohexanol and the corresponding hydrochloride
1-(2,4-difluorobenzyl)-2-(dimethylaminophenylmethyl)-cyclohexanol and the corresponding hydrochloride
1-(4-tert.-butylbenzyl)-2-[(3-chlorophenyl)dimethylaminomethyl]cyclohexanol and the corresponding hydrochloride
2-[dimethylamino-(3-phenoxyphenyl)methyl]-1-phenethyl-cyclohexanol and the corresponding hydrochloride
2-[dimethylamino-(3-phenoxyphenyl)methyl]-1-(3-trifluoromethylbenzyl)cyclohexanol and the corresponding hydrochloride
1-(2,5-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-(3,4-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-(2,3-difluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[(4-chlorophenyl)dimethylaminomethyl]cyclohexanol and the corresponding hydrochloride
1-dimethylamino-3-ethyl-2-methyl-1,5-diphenylpentane-3-ol and the corresponding hydrochloride
1-(2-chlorobenzyl)-2-[(2-chlorophenyl)-dimethylaminomethyl]cyclohexanol and the corresponding hydrochloride
1-benzyl-2-[(4-bromophenyl)dimethylaminomethyl]cyclohexanol and the corresponding hydrochloride
2-[(4-chlorophenyl)dimethylaminomethyl]-1-(4-trifluoromethylphenyl)cyclohexanol and the corresponding hydrochloride
2-[(4-chlorophenyl)dimethylaminomethyl]-1-(3-trifluoromethylbenzyl)cyclohexanol and the corresponding hydrochloride
1-(4-tert.-butylbenzyl)-2-[dimethylamino-(3-phenoxyphenyl)methyl]cyclohexanol and the corresponding hydrochloride
4-{dimethylamino-[2-hydroxy-2-(4-trifluoromethylphenyl)cyclohexyl]methyl}benzonitryl and the corresponding hydrochloride
2-(dimethylamino-o-tolylmethyl)-1-phenylcyclohexanol and the corresponding hydrochloride
1-benzyl-2-(dimethylamino-o-tolylmethyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(3-phenylpropyl)cyclohexanol and the corresponding hydrochloride
2-[(2-chlorophenyl)dimethylaminomethyl]-1-[2-(4-fluorophenyl)ethyl]cyclohexanol and the corresponding hydrochloride
2-dimethylaminothiophene-2-ylmethyl]-1-(3-trifluoromethylbenzyl)cyclolhexanol and the corresponding hydrochloride
Methyl-4-[2-(dimethylaminophenylmethyl)-1-hydroxycyclohexyl]benzoate and the corresponding hydrochloride
1-benzyl-2-(dimethylaminophenylmethyl)-4-phenylcyclhexanol and the corresponding hydrochloride
1-(4-bromophenyl)-2-(dimethylaminophenylmethyl)cyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-naphthalene-1-ylcyclohexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(2-methylsulfanylphenyl)cyclohexanol and the corresponding hydrochloride
1-benzyl-2-(dimethylaminonaphthalene-2-ylmethyl)cyclohexanol and the corresponding hydrochloride
1-benzyl-2-(dimethylaminonapentafluorophenylmethyl)cyclohexanol and the corresponding hydrochloride
1-benzyl-2-(phenylpiperidin-1-ylmethyl)cyclolhexanol and the corresponding hydrochloride
2-(dimethylaminophenylmethyl)-1-(4-trifluoromethylphenyl)cyclohexanol and the corresponding hydrochloride
3-(4-tert.-butylbenzyl)-1-dimethylamino-2-methyl-1-phenylpentan-3-ol and the corresponding hydrochloride
2-(dimethylamino-o-tolylmethyl)-1-phenethylcyclohexanol and the corresponding hydrochloride
1-(4-tert.-butylbenzyl)-2-[dimethylaminothiophen-2-ylmethyl]cyclohexanol and the corresponding hydrochloride
Compounds according to the invention are also compounds of the general formula I as diastereomers or enantiomers in the form of their bases or salts of physiologically compatible acids.
In a special embodiment of the invention the compounds according to the invention including the disclaimed compounds are used as a mixture of the enantiomers in non-equimolar amounts as active agent in a medicinal drug, optionally together with further active agents. In this case the proportion of one enantiomer is preferably between 5 and 45 wt. %.
The expression xe2x80x9cC1-6 alkylxe2x80x9d denotes within the scope of the present invention straight-chain or branched hydrocarbons with 1 to 6 carbon atoms. Methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, neopentyl and n-hexyl may be mentioned by way of example.
The expression xe2x80x9cC3-7 cycloalkylxe2x80x9d denotes within the scope of the present invention saturated cyclic hydrocarbons or straight-chain or branched alkyl radicals that contain saturated cyclic hydrocarbons, with a total of 3 to 7 carbon atoms. Cyclopropyl, cyclopropylmethyl, methylcyclopropyl, cyclobutyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl or cycloheptyl may be mentioned by way of example.
The expression xe2x80x9carylxe2x80x9d denotes within the scope of the present invention preferably aromatic ring systems, optionally singly or multiply substituted, which may optionally contain heteroatoms in the ring system. The aryl radicals are preferably singly or multiply substituted by the radicals R9 to R13. The preferably 5-membered or 6-membered unsaturated heterocyclic compounds, optionally condensed with further rings, optionally singly or multiply substituted may contain one or two heteroatoms such as nitrogen, oxygen and/or sulfur in the ring system.
There may be mentioned by way of example from the group of heteroaryl compounds: furan, thiophene, pyrrole, pyridine, pyrimidine, quinoline, isoquinoline, phthalazine or quinazoline.
Furthermore, processes for preparing the compound of the general formula I are also an object of the invention.
These processes for producing the compounds of the general formula I with the exception of 1-benzyl-2-(dimethylaminophenylmethyl)-cyclohexanol, its diastereomers and its enantiomers are characterised in that Mannich bases of the formula II are reacted with suitable nucleophilic compounds, preferably organometallic compounds R3Y in which Y denotes MgCl, MgBr, MgI or Li, at temperatures between xe2x88x9270xc2x0 C. and +110xc2x0 C. 
The conversion of a Mannich base of the formula II with a Grignard compound R3Y in which Y denotes MgCl, MgBr or MgI, or with an organolithium compound R3Li, may be carried out in an aliphatic ether, for example diethyl ether and/or tetrahydrofuran, a hydrocarbon, for example hexane or toluene, or mixtures of hydrocarbons and aliphatic ethers, at temperatures between xe2x88x9270xc2x0 C. and +110xc2x0 C. The preparation of a Grignard compound R3Y may be carried out with or without the addition of an entrainment reagent, preferably 1,2-dibromomethane. Alternatively, aromatic Grignard compounds R3Y may be obtained by reacting an aromatic iodide R3I with an organomagnesium compound, for example isopropylmagnesium chloride or diisopropylmagnesium, by iodine-magnesium exchange. organolithium compounds R3Li can be obtained from organohalogen compounds R3Z, in which Z denotes Cl, Br or I, by reaction with for example a n-butyllithium/liexane solution by halogen-lithium exchange.
In the reaction of a Manriich base of the formula II with an organometallic compound R3Y, depending on the reaction conditions preferably tertiary alcohols having the relative configuration of the formula Ia are obtained, in which the aminoarylmethyl group is arranged in the cis position relative to the hydroxl group when R1 and R2 form a ring system. In open-chain systems the analogous relative stereochemistry is obtained, which is specified as anti. The compounds of the general formula I, as well as their salts, for example the hydrochlorides, can be obtained in a diastereomer pure form by column chromatographic separation or by crystallisation. 
The Mannich bases of the formula II can be obtained by reacting enamines of the formula III with an imminium salt of the formula IV, in which Y denotes for example Clxe2x88x92, AlCl4xe2x88x92, Brxe2x88x92 or Ixe2x88x92. 
The enamines are prepared by processes known in the literature from ketones of the formula V arid secondary amines, for example dimethylamine, pyrrolidine, piperidine or morpholine (Acta Chem. Scand. B 38 (1984) 49-53). The imminium salts are prepared by processes known in the literature by reacting aminals of the formula VI with acid chlorides, for example acetyl chloride or thionyl chloride (Houben-Weylxe2x80x94Methoden der Organischen Chemie, E21b (1995) 1925-1929). 
The imminium salts of the formula IV need not be separated, but can be produced in situ and reacted with enamines of the formula III to form Mannich bases of the formula II (Agnew. Chem. 106 (1994) 2531-2533). On account of the enamine-imine tautomerism, which is similar to the keto-enol tautomerism, imines of the formula VII may also be used instead of the enamines of the formula III. Alternatively, ketones of the formula V can also be reacted directly with imminium salts of the formula IV.
Mannich bases of the formula II may however alos be prepared directly be reacting enamines of the formula III with an aromatic aldehyde of the formula VIII and a secondary amine HNR4R5, which may also be in the formula of the corresponding hydrochloride HNR4R5, HCl, in the presence of triethylamine, chlorotrimethylsilane and sodium iodide (Synlett (1997) 974-976). 
Depending on the reaction conditions, the Mannich bases of the formula II prepared by the aforedescribed processes are preferably obtained having the relative configuration of the formula IIa, in which the amino group is arranged anti to R1. The compounds of the formula lIa, as well as their salts, for example the hydrochlorides, can be obtained in a diastereomter pure form by crystallisation or by chromatographic separation. 
The formulation of Mannich bases of the formula II by 1,4-addition of secondary amines of the formula X to enones of the formula IX, which are obtained by the aldol condensation of ketones of the formula V with aromatic aldehydes of the formula VIII, proceeds in a less stereo-selective manner however (U.S. Pat. No. 4,017,637). This procedure is accordingly suitable for preparing the other possible stereoisomters. 
If chiral amines are used to prepare enamines of the formula III or imines of the formula VII, then enantiomer-enriched to enantiomer-pure Mannich bases of the formula II may be obtained in the following Mannich reaction (Houben-Weylxe2x80x94Methoden der Organischen Chemie, E21b (1995) 1925-1929). 3-amino-3-arylpropan-1-ol compounds of the general formula I in which R3 contains a phenolic substituent can be prepared for example from the corresponding methyl ether derivatives with diisobutylaluminium hydride in an aromatic hydrocarbon, for example toluene, at a temperature between 60xc2x0 C. and 130xc2x0 C. (Synthesis (1975) 617-630).
The compounds of the formula I can be converted in a manner known per se into their salts with physiologically compatible acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. The salt formulation is preferably carried out in a solvent, for example diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solution is suitable for preparing the hydrochlorides.
The substances corresponding to formula I are toxicologically safe, which means that they can be used as a pharmaceutical active agent in medicinal drugs. A further object of the invention are accordingly medicinal drugs containing as active agent at least one compound of the general formula I. The medicinal drugs according to the invention are preferably used as analgesics.
Biochemical investigation has shown that the substances according to the general formula I, in addition to their analgesic action, a pronounced affinity for the binding site 2 of the sodium channel (BTX binding), or the benzothiazepine and phenylalkylamine binding site of the L-type calcium channel (diltiazem and verapamil binding) and inhibit synaptosomal noradrenaline uptake (NA uptake inhibition). In addition to their particularly preferred use in the treatment of pain, the substances according to the general formula I are therefore also suitable for use as a local anaesthetic and/or anti-arrytlimic and/or anti-emetic and/or nootropic (neurotropic) and/or for the treatment/therapy of cardiovascular conditions and/or urinary incontinence and/or diarrhoea and/or pruritis and/or alcohol and/or narcotics and/or drug dependence and/or inflammation. As a rule the substances according to the invention are also suitable for treating depression and/or for improving alertness and attentiveness, and/or improving libido.
The analgesics according to the invention contain, in addition to at least one 3-amino-3-arylpropan-1-ol derivative of the formula I, excipients, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances as well as the amounts thereof to be used depends on whether the medicinal drug is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or topically, for example to treat skin infections, eye infections or infections of the mucous membranes. For oral application suitable preparations are in the form of tablets, sugar-coated pills, capsules, granular powders, drops, juices and syrups, while for parenteral, topical and inhalative application suitable forms are solutions, suspensions, easily reconstitutable dry preparations as well as sprays. Compounds according to the invention of the formula I in a sustained-release substance, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, are suitable percutaneous application preparations. Forms of preparations that can be used orally or percutaneously may produce a delayed release of the compounds according to the invention of formula I.
The amount of active agent to be administered to the patient depends on the patient""s weight, on the type of application, symptoms and the severity of the illness. Normally 0.5 to 500 mg/kg of at least one 3-amino-3-arylpropan-1-ol derivative of the formula I are administered.
Pharmacological Investigations
Analgesic Effect in the Writhing Test in Mice
The analgesic effect was investigated in the phenylquinone-induced writhing test in mice (as modified by I. C. Hendershot and J. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240). Male NMRI mice weighing 25 to 30 g were used for the test. Groups of 10 animals each received by intraperitoineal application, for each substance dose, 0.3 ml/mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Sigma Company, Deisenhofen; solution prepared with addition of 5% of ethanol and kept in a water bath at 45xc2x0 C.) 10 minutes after intravenous administration of the test substances. The animals were placed individually in observation cages. The number of pain-induced stretching movements (so-called writhing reactions=straightening of the body together with stretching of the rear extremities) was measured by means of a push-button counter 5 to 20 minutes after administration of the phenylquinone. Animals that had received only physiological saline solution served as controls. All substances were tested in the standard dose of 10 mg/kg. The percentage inhibition (% inhibition) of the writhing reaction produced by a substance was calculated according to the following formula:       %    ⁢          xe2x80x83        ⁢    inhibition    =      100    -                                                                      writhing                ⁢                                  xe2x80x83                                ⁢                reactions                                                                                        of                ⁢                                  xe2x80x83                                ⁢                the                ⁢                                  xe2x80x83                                ⁢                treated                ⁢                                  xe2x80x83                                ⁢                animals                                                                                                        writhing                ⁢                                  xe2x80x83                                ⁢                reactions                                                                                        of                ⁢                                  xe2x80x83                                ⁢                the                ⁢                                  xe2x80x83                                ⁢                control                ⁢                                  xe2x80x83                                ⁢                animals                                                        xc3x97      100      
For some substances the ED50 values were calculated with 95% confidence range of the writhing reaction by means of regression analysis (evaluation program from Martens EDV Service, Eckental) from the dose-dependent reduction in the writhing reactions compared to phenylquinone control groups investigated in parallel.
All the compounds according to the invention that were investigated exhibited a pronounced analgesic effect. The results are summarised in Table 1.
Investigations on the Noradrenaline Uptake Inhibition (NA Uptake Inhibition)
In order to carry out these in vitro studies, synaptosomes are isolated fresh from rat brains. In each case a so-called xe2x80x9cP2xe2x80x9d fraction is used, which is prepared according to the protocol of Gray and Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88). For the NA uptake these vesicular particles are isolated from the hypothalamus of male rat brains.
The following characteristic data were determined for the NA transporter:
NA uptake: Km=0.32xc2x10.11 xcexcM
(in each case N=4, i.e. mean valuesxc2x1SEM from 4 independent series of experiments that were carried out in the form of triple parallel experiments).
A detailed description of the methodology can be found in the literature (M. Ch. Frink, H.-H. Hennies, W. Englberger, M. Haurand and B Wilffert (1996) Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036).
Binding Investigations in the L Calcium Channel
Benzothiazepine Binding Site (Diltiazem Binding)
The biological membrane material was isolated from the rat cerebral cortex. [3H]-cis-(+)-diltiazem (5 nM in the assay) was used as ligand. The material was incubated for 20 minutes at 25xc2x0 C. The radioactivity that is measured in the presence of (xc2x1)-diltiazem (10xe2x88x926 M in the assay) is defined as non-specific binding. After completion of incubation the non-bound fraction of the radioactive ligand is separated by means of a filtration process using Whatman Glasfiber GF/B membranes. The membranes are washed and the radioactivity is then measured using a xcex2-counter. The method is based on the details published by Schoemaker and Langer (H. Schoemaker and S. Z. Langer (1985) Eur. J. Pharmacol. 111, 273-277). The KD value for this high-affinity binding site was 4.10xc2x10.75 nM (N=3, i.e. mean valuesxc2x1SEM from 3 independent series of experiments that had been carried out in triple parallel experiments).
Phenylalkylamine Binding Site (Verapamil Binding)
The biological material (ion channel particles) was prepared on the basis of the publication of Reynolds, Gould and Snyder (I. J. Reynolds, R. J. Gould and S. H. Snyder (1983) J. Pharmacol. 95, 319-321).
N-methyl-[3H]-verapamil (2 nM in the assay) was used as radioligand. The radioactivity that is measured in the presence of non-radioactive verapamil (10xe2x88x924 M in the assay) is defined as non-specific binding. The material was incubated at 25xc2x0 C. for 45 minutes. The material was then filtered using a Whatman GF/B filter, followed by washing. The radioactivity remaining on the filter (ion channel binding) was measured using a xcex2-counter.
The KD value for this binding site was found to be 138.6 nM (N=2, i.e. mean values from 2 independent series of experiments that had been carried out in the form of triple parallel experiments).
Binding Investigations in the Sodium Channel
Binding Site 2 (BTX Binding)
The binding site 2 of the sodium channel is the so-called batrachotoxin (BTX) binding site. [3H]-batrachlotoxin A20 xcex1-benzoate (10 nM in the assay) was used as ligand. These ion channel particles (synaptosomes) were concentrated from rat cerebral cortex according to the procedure of Gray and Whittaker (E. G. Gray and V. P. Whittaker (1962) J. Anat. 76, 79-88). The radioactivity that is measured in the presence of veratridine (0.3 mM in the assay) is defined as non-specific binding. The material was incubated at 37xc2x0 C. for 120 minutes. The assay conditions are carried out according to the protocol published by Pauwels, Leysen and Laduron (P. J. Pauwels, J. E. Leysen and P. M. Laduron (1986) Eur. J. Pharmacol. 124, 291-298).
The KD value for this binding site is 24.63xc2x11.56 nM. (N=3, i.e. mean valuesxc2x1SEM from 3 independent series of experiments that were carried out in the form of triple parallel experiments).
Evaluation
In addition to the percentage inhibition of the test systems at fixed test substance concentrations (NA uptake: 1 xcexcM in the assay; ion channel assays: 10 M in the assay), the dose dependencies were investigated. For this purpose IC50 values are obtained, which can be converted to inhibitor constants (Ki) according to the xe2x80x9cCheng-Prusoff equationxe2x80x9d (Y. C. Clieng and W. H. Prusoff (1973) Biochem. Pharmacol. 22, 3099-3108). The IC50 values were obtained by means of the computer program xe2x80x9cFigure Pxe2x80x9d (version 6.0, Biosoft, Cambridge, England). Km values were calculated according to Lineweaver and Burk (H. Lineweaver and D. Burk (1934) J. Am. Chem. Soc. 56, 658-666). The xe2x80x9cLigandxe2x80x9d computer program (version 4, Biosoft, England) was used to obtain Ken values.
The results of the biochemical investigations are summarised in Table 2.